H. Koyama et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3347–3351
3351
K.; Moller, D. E.; Heck, J. V.; Sahoo, S. P. Bioorg. Med.
Chem. Lett. 2003, 13, 1801.
20. Rybczynski, P. J.; Zeck, R. E.; Combs, D. W.; Turchi, I.;
Burris, T. P.; Xu, J. X.; Yang, M.; Dermarest, K. T.
Bioorg. Med. Chem. Lett. 2003, 13, 2359.
vastatin were significantly altered by co-administra-
tion.34 It appears that the two different mechanisms of
cholesterol lowering, PPARa activation and HMG-
CoA reductase inhibition, can work in concert.
21. Kuroda, M.; Mimaki, Y.; Sashida, Y.; Mae, T.; Kishida,
H.; Nishiyama, T.; Tsukagawa, M.; Konishi, E.; Takah-
ashi, K.; Kawada, T.; Nakagawa, K.; Kitahara, M.
Bioorg. Med. Chem. Lett. 2003, 13, 4267.
22. Acton III, J. J.; Black, R. M.; Jones, A. B.; Moller, D.
E.; Colwell, L.; Doebber, T. W.; MacNaul, K. L.;
Berger, J.; Wood, H. B. Bioorg. Med. Chem. Lett.
2005, 15, 357.
In conclusion, by taking advantages of our accumulated
knowledge of chromane-2-carboxylic acid SAR with
PPARa and c, we were able to identify a class of highly
potent and selective PPARa agonists. The optimized
compound 43 exhibited robust cholesterol lowering in
the hamster and dog models.35
23. Brown, P. J.; Wingar, D. A.; Plunket, K. D.; Moore, L. B.;
Lewis, M. C.; Wilson, J. G.; Sundseth, S. S.; Koble, C. S.;
Wu, Z.; Chapman, J. M.; Lehmann, J. M.; Kliewer, S. A.;
Willson, T. M. J. Med. Chem. 1999, 42, 3785.
24. Brown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.;
Winegar, D. A.; Wilson, J. G.; Wilkinson, W. O.; Ittoop,
O. R.; Willson, T. M. Bioorg. Med. Chem. Lett. 2001, 11,
1225.
Acknowledgments
Authors thank Mr. Joseph F. Leone, Mr. Robert A.
Frankshun, and Dr. Philip Eskola for large scale syn-
thetic support, and Drs. William P. Feeney and Susan
A. Iliff for their support in pharmacological evaluation
of compounds.
25. Miyachi, H.; Nomura, M.; Tanase, T.; Takahashi, Y.; Ide,
T.; Tsunoda, M.; Murakami, K.; Awano, K. Bioorg. Med.
Chem. Lett. 2002, 12, 77.
References and notes
26. Nomura, M.; Tanase, T.; Ide, T.; Tsunoda, M.; Suzuki,
M.; Uchiki, H.; Murakami, K.; Miyachi, H. J. Med.
Chem. 2003, 46, 3581.
27. Xu, Y.; Mayhugh, D.; Saeed, A.; Wang, X.; Thompson,
R. C.; Dominanni, S. J.; Kauffman, R. F.; Singh, J.; Bean,
J. S.; Bensch, W. R.; Barr, R. J.; Osborne, J.; Montrose-
Rafizadeh, C.; Zink, R. W.; Yumbie, N. P.; Huang, N.;
Luffer-Atlas, D.; Runga, D.; Maise, D. E.; Mantlo, N. B.
J. Med. Chem. 2003, 46, 5121.
28. Koyama, H.; Miller, D. J.; Boueres, J. K.; Desai, R. C.;
Jones, A. B.; Berger, J. P.; MacNaul, K. L.; Kelly, L. J.;
Doebber, T. W.; Wu, M. S.; Zhou, G.; Wang, P.-R.;
Ippolito, M. C.; Chao, Y.-S.; Agrawal, A. K.; Franklin,
R.; Heck, J. V.; Wright, S. D.; Moller, D. E.; Sahoo, S. P.
J. Med. Chem. 2004, 47, 3255.
29. Sahoo, S. P.; Koyama, H.; Miller, D. J.; Boueres, J. K.;
Desai, R. C. US Patent 6,645,997, 2003; Chem. Abstr.
2002, 136, 279341.
1. Biondi-Zoccai, G. G. L.; Abbate, A.; Liuzzio, G.; Bias-
ucci, L. M. J. Am. Coll. Cardiol. 2003, 41, 1071.
2. Ginsberg, H. N.; Stalenhof, A. F. J. Cariovasc. Risk 2003,
10, 121.
3. Scandinavian Simvastatin Survival Study Group Lancet,
1994, 344, 1383.
4. Vosper, H.; Khoudoli, A. G.; Graham, T. L.; Palmer, C.
N. A. Pharm. Therap. 2002, 95, 47.
5. Fruchart, J.-C.; Staels, B.; Duriez, P. Curr. Pharm. Res.
2001, 5, 345.
6. Francis, G. A.; Annicotte, J.-S.; Auwerx, J. Curr. Opin.
Pharmacol. 2003, 41, 393.
7. Neve, B. P.; Fruchart, J.-C.; Staels, B. Biochem. Pharma-
col. 2000, 60, 1245.
8. Duval, C.; Chinetti, G.; Trottein, F.; Fruchart, J.-C.;
Staels, B. Trends Mol. Med. 2002, 8, 422.
30. Sahoo, S. P.; Koyama, H.; Boueres, J. K.; Miller, D. J.;
Desai, R. C. US Patent 6,713,508, 2004; Chem. Abstr.
2002, 137, 140435.
9. Fruchart, J.-C. Am. J. Cardiol. 2001, 88, 24N.
10. Barish, G. D.; Evans, R. M. Trends Endocri. Metabol.
2004, 15, 158.
31. Agrawal, A. K.; Hop, C. E. C. A.; Pang, J.; Elipe, M. V.
S.; Desai, R. C.; Leung, K. H.; Franklin, R. B. J. Pharm.
Biomed. Anal. 2005, 37, 351.
11. Issemann, I.; Green, S. Nature 1990, 347, 645.
12. Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B.
R. J. Med. Chem. 2000, 43, 527.
32. Berger, J. P.; Petro, A. E.; MacNaul, K. L.; Kelly, L. J.;
Zhang, B. B.; Richards, K.; Elbrecht, A.; Johnson, B. A.;
Zhou, G.; Doebber, T. W.; Biswas, C.; Parikh, M.;
Sharma, N.; Tanem, M.; Thompson, M.; Venture, J.;
Adams, A. D.; Mosely, R.; Surwit, R. S.; Moller, D. E.
Mol. Endocrinol. 2003, 17, 662.
13. Berger, J. P.; Moller, D. E. Annu. Rev. Med. 2002, 53, 527.
14. Kersten, S.; Desvergne, B. Nature 2000, 405, 421.
15. Desvergne, B.; Wahli, W. Endocr. Rev. 1999, 20, 649.
16. Yanagisawa, H.; Takamura, M.; Yamada, E.; Fujita, S.;
Fujiwara, T.; Yachi, M.; Isobe, A.; Hagisawa, Y. Bioorg.
Med. Chem. Lett. 2000, 10, 373.
33. Berger, J.; Leibowitz, M. D.; Doebber, T. W.; Elbrecht,
A.; Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.;
Hayes, N. S.; Li, Y.; Tanem, M.; Venture, J.; Wu, S. M.;
Berger, G. D.; Mosley, R.; Marquis, R.; Santini, C.;
Sahoo, S. P.; Tolman, R. L.; Smith, R. G.; Moller, D. E. J.
Biol. Chem. 1999, 274, 6718.
17. Momose, Y.; Maekawa, T.; Yamano, T.; Kawada, M.;
Okada, H.; Ikeda, H.; Sohda, T. J. Med. Chem. 2002, 45,
1518.
18. Thor, M.; Beierlein, K.; Dykes, G.; Gustavsson, A.-L.;
Heidrich, J.; Jendeberg, L.; Lindqvist, B.; Pegurier, C.;
Roussel, P.; Slater, M.; Svesson, S.; Sydow-Ba¨ckman, M.;
Thornstro¨m, U.; Uppenberg, J. Bioorg. Med. Chem. Lett.
2002, 12, 3565.
34. Agrawal, A. K. private communication.
35. Sahoo, S. P. New Therapies for Atherosclerosis. Part of
this work was presented at the 225th American Chemical
Society National Meeting, New Orleans, LA, March 2003;
Oral paper 153.
19. Koyama, H.; Boureres, J. K.; Han, W.; Metzger, E. J.;
Bergman, J. P.; Gratale, D. F.; Miller, D. J.; Tolman, R.
L.; MacNaul, K. L.; Berger, J. P.; Doebber, T. W.; Leung,